1. Technical Field
The invention relates to MMP-13 metalloprotease inhibiting compounds.
2. Background Information
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases. MMPs function to degrade extracellular matrix proteins and are involved in the cleavage of cell surface receptors, growth factors, cell-adhesion molecules, cytokines and chemokines, as well as other MMPs and unrelated proteases. MMPs are also thought to play a major role on cellular processes such as proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis and host defense. (Hu J. et al. Nat. Rev. Drug Discov. 2007 6:480-498; Ramnath N. and Creaven P. J. Curr. Oncol. Rep. 2004 6:96-102). MMPs are therefore targets for therapeutic diseases including rheumatoid arthritis, osteoarthritis, osteoporosis, peridontitis, atherosclerosis, congestive heart failure, multiple sclerosis and tumor metastasis.
The mammalian MMP family includes more than 20 members that share common structural attributes: a propeptide domain, a catalytic domain and a C-terminal hemopexin-like domain (except for MMP-7 and MMP-26). The function of MMPs in health and disease is regulated in multiple ways. MMPs are secreted as inactive proproteins which are activated when the propepetide domain is cleaved by extracellular proteinases or destabilized by protein-protein interactions. The activity of MMPs is also regulated by tissue inhibitors of metalloproteinases (TIMPs) which bind to the catalytic site of MMPs. The production of MMPs is also regulated at the level of transcription by specific signals that are temporally limited and spatially confined. (Parks W. C. et al 2004, Nat. Rev. Immunol. 2004 4:617-629).
The collagenase subset of the matrix metalloproteinase family, comprising MMP-1 (collagenase 1), MMP-8 (collagenase 2), MMP-13 (collagenase 3) and more recently MMP-14, catalyzes the initial cleavage of collagen types I, II, III, V and X (Parks W. C. et al Nat. Rev. Immunol. 2004 4:617-629). MMP-13 cleaves type II collagen more efficiently than types I and III and is capable of cleaving multiple extracellular matrix proteins in addition to fibrillar collagens (Leeman M. F. et al Crit. Rev. Biochem. Mol. Biol. 2003 37:149-166). MMP-13 is the most proficient catalyst of collagen type II degradation, the committed step in articular cartilage degradation and progressive joint damage associated with RA and osteoarthritis (OA). In the case of collagen type II (90-95% of articular cartilage), the triple helix is cleaved at position G775/L776 at least an order of magnitude faster by MMP-13 than by MMP-1 and MMP-8 (Billinghurst, R. C. et al. J. Clin. Invest. 1997 99:1534-1545). Cleavage of collagen type II triple helix at position G775/L776 by MMP-13 triggers the initial unfolding of the molecule, rendering it susceptible to catalytic degradation by additional members of the MMP family. The superior catalytic efficiency of MMP-13 for collagen type II degradation, coupled with induced expression of MMP-13 in synovial fibroblasts and chondrocytes associated with rheumatoid arthritis (RA) and osteoarthritis (OA) pathology, is consistent with MMP-13 being responsible for catalyzing the committed step in cartilage degradation associated with RA and OA (Mitchell, P. G. et al. 1996 J. Clin. Invest. 1996 97:761-768; Moore, B. A. et al, Biochim Biophys. Acta 2000 1502:307-318).
Furthermore, transient adenoviral expression of MMP-13 in mouse knee chondrocytes and synoviocytes induces a transient arthritic condition, including recruitment of inflammatory cells, and up-regulation of inflammatory cytokine mRNA (Oronen, K. et al. 2004. Ann. Rheum. Dis. 63, 656-664). Transgenic mice with a constitutively active form of human MMP-13 in cartilage exhibit augmented cleavage of type II collagen and leading to an osteoarthritic-like phenotype with marked cartilage degradation and synovial hyperplasia (Neuhold, L. A. et al 2001 J. Clin. Invest. 107, 35-44). These in vivo validation studies further support the role of MMP-13 in RA and OA pathogenesis.